3.4 | Case Study: D227Y of CD23
CD23 is the low-affinity receptor for IgE. It is expressed in several hematopoietic cells surface (Acharya et al., 2010), such as lymphocytes (Delespesse et al., 1991), monocytes (Vercelli et al., 1988), follicular dendritic cells (Krauss, Mayer, Rank, & Rieber, 1993; Rieber, Rank, Kohler, & Krauss, 1993), and bone marrow stromal cells (Fourcade et al., 1992). Several stimuli regulate the CD23 expression, which is the critical factor for B-cell activation, growth, and IgE production (OMIM#151445). The D227Y mutation generated from FCER2 genetic altered had been reported in head and neck squamous cell carcinoma (HNSCC) (Stransky et al., 2011) and the colorectal neuroendocrine carcinomas mutational analyses project (Woischke et al., 2017). D227 located in one of the conserved double-loop, which is the interface between CD23 and the carbohydrate protein, Fc\(\varepsilon\)3-4. Moreover, Ca2+ is a regulated ligand for CD23 binding affinity. With Ca2+ binding, the loop1 and loop4 would change the conformation and increase the binding affinity. D227 (loop1) and D258 (loop4) would form the additional salt bridges between CD23 and Fc\(\varepsilon\)3-4 (Dhaliwal et al., 2013; Yuan et al., 2013). Though there are other bounds involved in CD23 and Fc\(\varepsilon\)3-4 binding, the D227Y would affect the binding affinity and affect the IgE antitumor function (Figure 3).
Figure 4 shows the boxplot of the micro-environment descriptors in ASP altered to TYR sub-group. The distribution of cancer-related SAVs in several descriptors has a significant difference comparing to the neutral SAVs, and get a 95% confidence interval by z-test. The cancer-related SAVs are located in the relatively low packing density region, whether \(C_{\alpha}\) atoms, nitrogen, or oxygen in a single SAV chain and whole protein. In the case of D227Y in CD23, it also has low WCN value in a single SAV chain but has relatively high WCN value in whole protein or other chains (Figure 4 a, b, and c). It is because D227 is located in the interface of CD23 and Fc\(\varepsilon\)3-4 and is involved in the binding. Subsequently, the cancer-related SAVs has the lower distributions of specific tendency of H -neutral (AGPHY),V -small (GASCTPD), V -large(MHKFRYW), Z -low polarizability(GASDT), Z -high polarizability (KMHFRYW),P -neutral polarity (PATGS), F -basic (HKR),F -nonpolar (AFILMPVW), E -basic (HKR), E -aromatic (FWY) and E -aliphatic1 (AGP) of neighboring amino acid. This unique surrounding pattern is also found in the cases D227Y of CD23 (Figure 4 d, e, f, g, h, and i).